The objective of this proposal is the elucidation of the biochemial basis in L1210 cells for the synergism of four oncolytic 2-drug combinations, three of which have previously been reported from this laboratory and a fourth for which preliminary investigations have been initiated. In the studies proposed with methotrexate (MTX) plus cytosine arabinoside (Ara-C), the aim is to prove conclusively that the induced alterations in the size of the intracellular pools of pyrimidine deoxyribonucleotides are responsible for the prolonged intracellular retention of Ara-C nucleotides and to show how this prolonged retention produces the dosage-related oncolytic interaction between the drugs observed in the treatment of L1210 leukemia. The aim of the studies with adriamycin (Adria) plus cyclophosphamide (Cyclo) is to identify the biochemical basis for the reciprocal potentiation between these drugs in combination which is postulated to result from a modification of DNA, and then to identify the basis for the previously observed negative, dosage-related interaction between the drugs, which may require examination of the pharmacokinetics of the drugs in combination. With VM26, a 4'-demethylepipodophyllotoxin, plus Ara-C the aim is to understand how the fragmentation of DNA by VM26 potentiates the oncolytic activity of Ara-C that was observed in the treatment of L1210 leukemia. The requisite survival studies, for the pharmacologic investigations proposed with VM26 plus carmustine (BCNU), have not been completed, but the projected biochemical approach will require an examination of the effect of this drug combination on DNA. It is postulated that this combination will provide a broader understanding of the response to Adria plus Cyclo. The significance of the studies proposed arises from the information that will be provided on the pharmacologic basis about synergism by these combinations which are increasingly clinically emphasized by colleagues in the treatment of recurrent neoplastic diseases of childhood after relapse on conventional treatment.